Abstract
BackgroundAerobic glycolysis, discovered by Otto Warburg, is a hallmark of cancer metabolism even though not yet fully understood. The low activity of the cancerous pyruvate kinase isozyme (M2) is thought to play an important role by facilitating the conversion of glycolytic intermediates to other anabolic pathways to support tumors’ high proliferation rate.MethodsFive breast cancer cell lines representing different molecular subtypes were used in this study where real time measurements of cellular bioenergetics and immunoblotting analysis of energy- and nutrient-sensing pathways were employed to investigate the potential effects of PKM2 allosteric activator (DASA-58) in glucose rewiring.ResultsIn this study, we show that DASA-58 can induce pyruvate kinase activity in breast cancer cells without affecting the overall cell survival. The drug is also able to reduce TXNIP levels (an intracellular glucose sensor) probably through depletion of upstream glycolytic metabolites and independent of AMPK and ER signaling. AMPK shows an induction in phosphorylation (T172) in response to treatment an effect that can be potentiated by combining DASA-58 with other metabolic inhibitors.ConclusionsAltogether, the multifaceted metabolic reprogramming induced by DASA-58 in breast cancer cells increases their susceptibility to other therapeutics suggesting the suitability of the intracellular glucose sensor TXNIP as a marker of PK activity.
Highlights
Aerobic glycolysis, discovered by Otto Warburg, is a hallmark of cancer metabolism even though not yet fully understood
It is worth mentioning that Pyruvate kinase (PK) activity was significantly different between MCF7 and MDA MB 231, for example, even though Pyruvate kinase M2 (PKM2) levels were comparable between these two cell lines
In this study, we investigate the efficacy of PKM2 pharmacological activation on glucose metabolism in breast cancer cells
Summary
Aerobic glycolysis, discovered by Otto Warburg, is a hallmark of cancer metabolism even though not yet fully understood. Despite the low efficiency of glycolysis in terms of ATP production in comparison to oxidative phosphorylation, many cancers adopt the glycolytic phenotype [3]. The aforementioned reasons propose the importance of a strict control of glycolysis in cancer cells and the ability to tune glycolytic metabolites based on the cellular needs. Another level of regulating PKM2 activity is mediated by the availability of serine–serine shown to enhance the affinity of PKM2 to PEP, and under serine abundant conditions, PKM2 is “active,” but when serine is scarce PKM2 activity drops allowing for upstream metabolites to be shunted into the serine biosynthesis pathway [13]
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